Rh(II)-catalyzed intramolecular N-H insertion of D-glucose-derived δ-amino α-diazo β-ketoester: Synthesis of pyrrolidine iminosugars

Article abstract of DOI:10.1055/s-2007-970743

The rhodium acetate catalyzed reaction of D-glucose-derived δ-amino α-diazo β-ketoester allows a stereoselective β-facial intramolecular N-H insertion reaction that leads to formation of the bicyclic pyrrolidinone ring skeleton in high yield. The sugar-su

Full text of DOI:10.1055/s-2007-970743

LETTER
559
Rh(II)-Catalyzed Intramolecular N–H Insertion of D-Glucose-Derived
d-Amino a-Diazo b-Ketoester: Synthesis of Pyrrolidine Iminosugars
S
ynthesis of Pyrro
i
lidine
I
n
minosugars od P. Vyavahare,a Subrata Chattopadhyay,b Vedavati G. Puranik,c Dilip D. Dhavale*a
a
b
c
Garware Research Centre, Department of Chemistry, University of Pune, Pune 411007, India
Bio-Organic Division, Bhaba Atomic Research Centre, Mumbai 400085, India
Center for Materials Characterization, National Chemical Laboratory, Pune 411008, India
Fax +91(20)25691728; E-mail: ddd@chem.unipune.ernet.in
Received 3 November 2006
This class of compounds, especially the naturally occur-
ring (2R,3R,4R,5R)-2,5-dihydroxymethyl-3,4-dihydroxy-
pyrrolidine (DMDP; 1),10 2,5-dideoxy-2,5-imino-D-
glucitol [(2R,3R,4R,5S)-2,5-dihydroxymethyl-3,4-dihy-
Abstract: The rhodium acetate catalyzed reaction of D-glucose-de-
rived d-amino a-diazo b-ketoester allows a stereoselective b-facial
intramolecular N–H insertion reaction that leads to formation of the
bicyclic pyrrolidinone ring skeleton in high yield. The sugar-sub-
stituted pyrrolidinone thus obtained was elaborated to allow the droxypyrrolidine (DGDP), 2],11 2,5-dideoxy-2,5-imino-
D/L-glycero-D-mannoheptitol (homoDMDP; 3),12,13
synthesis of promising glycosidase inhibitors, namely, 2,5-dideoxy-
2,5-imino-L-glycero-a-D-galactoheptitol and 2,5-dideoxy-2,5-imi-
no-D-galactitol.
and 2,5-dideoxy-2,5-imino-D/L-glycero-D-galactoheptitol
(4)13 (in both 3 and 4, D- or L-glycero configuration is un-
Key words: alkaloids, azasugars, carbohydrates, pyrrolidines,
rhodium carbenoid, N–H insertion
known) alkaloids are promising glycosidase inhibitors
with potential antibacterial, antiviral, antimetastatic, and
antidiabetes activities (Figure 1).11,14 These pyrrolidine
iminosugars have also been used as starting materials for
The presence of the pyrrolidine ring in natural products1
the preparation of other polyhydroxy alkaloids of the
pyrrolizidine family.15 Moreover, C2-symmetrical deriva-
tives of DMDP have been utilized as chiral ligands and as
catalysts for a variety of chemical transformations.16
as well as its utility in asymmetric synthesis as a chiral
auxillary2 and ligand3 has led to a number of intermolecu-
lar and intramolecular synthetic methodologies for its
construction.4 Amongst the intramolecular pathways,5 the
metal carbenoid mediated N–H insertion reaction of d-
amino a-diazo b-ketoester (or phosphonates) is promising
and has led to the formation of pyrrolidinones in good
yield.6 Although this methodology is widely utilized in
organic synthesis, its applicability to a sugar substrate is
unknown. This is probably due to the difficulty in getting
the appropriate substrates with the combination of d-ami-
no a-diazo b-keto functionality in a sugar skeleton. In this
respect, we have recently reported the synthesis of D-glu-
cose-derived a-diazo b-keto ester7 and demonstrated8 that
the rhodium carbenoid generated bicyclic oxonium ylide
undergoes [1,2]-migration leading to the formation of the
1,5-dioxabicyclo[3.3.0]octane ring skeleton which is an
intermediate for the synthesis of a griseolic acid analogue.
Inspired with this observation and as a part of our interest
in the area of iminosugars,9 we thought of preparing an
appropriate sugar substrate having d-amino a-diazo b-
ketoester functionality that could be used to probe the
rhodium carbenoid mediated intramolecular N–H inser-
tion methodology. The bicyclic pyrrolidinone ring skele-
ton would have a sugar appended on one side and the
b-ketoester functionality on the other (both useful for the
conversion into hydroxylated carbon frameworks), and
could be elaborated for the synthesis of polyhydroxylated
pyrrolidine alkaloids.
We now describe our results in the rhodium acetate cata-
lyzed intramolecular N–H insertion reaction of D-glucose-
derived d-amino a-diazo b-ketoester 8 for the stereoselec-
tive formation of the bicyclic pyrrolidinone ring. The
pyrrolidinone ring thus obtained was elaborated to pyrrol-
idine iminosugars, namely, 2,5-dideoxy-2,5-imino-L-
glycero-a-D-galactoheptitol (12) and 2,5-dideoxy-2,5-
imino-D-galactitol [(2R,3S,4R,5S)-2,5-dihydroxymethyl-
3,4-dihydroxypyrrolidine (DGADP), 14], the potent a-
galactosidase inhibitor with Ki = 5 × 10–8 M.17 The well-
defined L-glycero configuration in the synthesis of a-D-
galactoheptitol 12 is informative to reveal the identity of
4, isolated from the Scilla sibirica, as the D- or L-glycero
analogue.
As shown in Scheme 1, D-glucose was converted into 3-
benzyloxycarbonylamino-3-deoxy-1,2-O-isopropylidene-
a-D-glucofuranose (5) following a literature method.18
HO
OH
HO
OH
HO
HO
OH
OH
N
H
N
H
1
2
HO
OH
HO
OH
3
2
6
HO
HO
1
5
4
OH
OH
N
H
N
H
OH
OH
SYNLETT 2007, No. 4, pp 0559–0562
0
1.
0
3.
2
0
0
7
3
4
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-970743; Art ID: D32606ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Naturally occurring polyhydroxy pyrrolidine alkaloids

560
V. P. Vyavahare et al.
LETTER
Oxidative cleavage of diol 5 with sodium metaperiodate Compound 10 is an immediate precursor for the target
in acetone–water afforded aldehyde 6 in 60% overall yield molecules. Thus, removal of the 1,2-acetonide functional-
from glucose.19 A reaction of 6 with ethyl diazoacetate in ity in 10 with TFA–water (3:2) at room temperature fol-
the presence of a catalytic amount of ZnCl2, in dichlo- lowed by treatment with LiAlH4 in THF afforded the
romethane, afforded the b-ketoester 7 in 81% yield which aminol 1122 which on hydrogenolysis (10% Pd/C in meth-
on reaction with methanesulfonyl azide (1.1 equiv) and anol) afforded 2,5-dideoxy-2,5-imino-L-glycero-a-D-ga-
1
triethylamine provided the requisite D-glucose-derived lactoheptitol (12) as a viscous liquid. The H and 13C
NCbz-protected d-amino a-diazo b-ketoester 8 in 87% NMR data and specific rotation of 12 did not match with
yield. In the key reaction, the Rh(II) acetate catalyzed re- that of naturally occurring 4 (in which the absolute config-
action of 8 in refluxing benzene afforded bicyclic pyrroli- uration at C6 is unknown). As compounds 12 and 4 are
dinone 9 in 78% yield. At this stage, we were unable to C6-epimers and compound 12 was found to have the 6R
assign the absolute configuration of the newly generated configuration, the 6S absolute configuration was therefore
1
stereocentre at C6, since the H NMR spectrum showed assigned to the natural product.
doubling of signals due to the presence of the NCbz func-
tionality and the presence of keto–enol tautomerism.
However, removal of the NCbz group in 9 by hydrogenol-
To complete the synthesis of 14, hydrolysis of the 1,2-ac-
etonide functionality in 10 with TFA–water (3:2) at room
temperature followed by treatment with sodium meta-
ysis (10% Pd/C in methanol) followed by reduction with
20
LiAlH4 and perbenzylation21 at 80 °C for 48 hours fur-
HO
HO
nished the major product 10 as a white solid in 68% over-
O
all yield in three steps. In the 1H NMR spectrum of 10, the
appearance of H-5 as a doublet of doublets with a large
vicinal coupling constant (J5,6 = 6.6 Hz and J4,5 = 4.8 Hz)
suggested the cis relation between H-5 and H-6, and be-
tween H-5 and H-4. In the NOE experiment, the irradia-
tion of H-5 showed a NOE interaction of H-5 with H-4
and H-6 indicating the cis-relative orientation of H-5 with
respect to H-6 and H-4. This fact was further confirmed
by the single crystal X-ray analysis of 10 (Figure 2) and
established the absolute configuration at the newly gener-
ated streocentres as 5R and 6S. In the above reaction se-
quence, the first step in the formation of 10 presumably
involved stereoselective b-facial intramolecular N–H in-
sertion in 8 to give 9 and highly diastereoselective (88%
de) reduction of the 5-keto functionality in 9, from the
convex facial attack of LiAlH4, to yield the D-gluco iso-
mer that on perbenzylation gave 10.
NHR
(i)
H
D-glucose
R = Cbz
O
O
O
O
5
(ii)
O
O
O
OHC
H
O
NHR
O
NHR
EtO
EtO
(iii)
H
O
O
O
6
7
(iv)
O
O
O
O
NHR
(v)
O
H
N
R
N2
H
O
O
H
O
EtO
8
9
(vi)
R1O
OH
BnO
O
R1O
(vii)
H
O
OH
N
R1
N
H
O
10
Bn
BnO
OH
11 R1 = Bn
12 R1 = H
(viii)
(ix)
HO
OH
_
R2O
OH
(xi)
HO
R2O
OH
OH
N
N
R2
Cl
H
H
15
13 R2 = Bn
14 R2 = H
(x)
Scheme 1 Reagents and conditions: (i) See ref. 18; (ii) NaIO4, ace-
tone–H2O, 0 °C, 2 h, 90%; (iii) ethylene diamine (EDA; 1.5 equiv),
ZnCl2, CH2Cl2, 25 °C, 2 h, 81%; (iv) MsN3 (1.1 equiv), Et3N (2
equiv), MeCN, 25 °C, 2 h, 87%; (v) Rh2(OAc)4 (0.003 equiv), C6H6,
25 °C, 20 min, 78%; (vi) (a) H2, 10% Pd/C, MeOH, 80 psi,12 h; (b)
LiAlH4, THF, 0 °C, 2 h; (c) NaH, BnBr, THF, 80 °C, 48 h, 68%; (vii)
(a) TFA–H2O (3:2), 0–25 °C, 3 h; (b) LiAlH4, THF, 0 °C, 2 h, 81%;
(viii) H2, 10% Pd/C, MeOH, 80 psi, 24 h, 85%; (ix) (a) TFA–H2O
(3:2), 0–25 °C, 3 h; (b) NaIO4, acetone–H2O, 0 °C, 1.5 h; (c) LiAlH4,
THF, 0 °C, 2 h, 52%; (x) H2, 10% Pd/C, MeOH, 80 psi, 24 h, 83%;
(xi) MeOH·HCl, 0–25 °C, 3 h, 89%.
Figure 2 ORTEP diagram of compound 10
Synlett 2007, No. 4, 559–562 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyrrolidine Iminosugars
561
Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience: New York, 1998.
periodate afforded the one-carbon degraded aminal that
was directly reduced with sodium borohydride in metha-
nol to give amino diol 13 in 52% yield. Hydrogenolysis
(10% Pd/C in methanol) of 13 gave 2,5-dideoxy-2,5-imi-
no-D-galactitol (14) as a viscous liquid. The reaction of 14
with MeOH·HCl afforded the corresponding hydrochlo-
ride salt 15 as a sticky solid. The 1H and 13C NMR data of
14 and 15 were found to be in consonance with those re-
ported.17,23
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In conclusion, we have demonstrated: (i) the first example
of the rhodium carbenoid mediated intramolecular N–H
insertion in sugar substrates leading to the formation of
the bicyclic pyrrolidinone ring skeleton, (ii) the synthesis
of potential glycosidase inhibitory pyrrolidine iminosug-
ars 12 and 14,24 (iii) that the naturally occurring 4 has the
D-glycero-D-galactoheptitol configuration.
(7) (a) Dhavale, D. D.; Bhujbal, N. N.; Joshi, P.; Desai, S. G.
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Acknowledgment
(8) Karche, N. P.; Jachak, S. M.; Dhavale, D. D. J. Org. Chem.
2003, 68, 4531.
We thank the Pune University–BARC collaborative research pro-
gram and CSIR-New Delhi (Project no. 01(1906)/03/EMR-II) for
financial support. We are grateful to Prof. M. S. Wadia for helpful
discussion.
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Synlett 2007, No. 4, 559–562 © Thieme Stuttgart · New York

562
V. P. Vyavahare et al.
LETTER
(20) The formation of 10 as a major product in 94% yield could
be explained on the basis of the hydride delivery in LiAlH4,
reducing from the convex face; the concave face attack of
hydride afforded the corresponding C-5 epimeric compound
in 6% yield as a minor product as evident from the 1H and
13C NMR spectral data.
(21) Perbenzylation at room temperature under a variety of
reaction conditions for prolonged time afforded a mixture of
mono-, di- and tribenzylated products.
(22) The NaBH4 (2.5 equiv) reduction of an anomeric mixture of
hemiacetal was sluggish and led to only 50% conversion into
the corresponding alcohol. Use of an excess amount of
NaBH4 did not improve the yield of the product.
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(br), 1750, 1660 cm–1. Anal. Calcd for C20H23NO8 (405):
C, 59.25; H, 5.72. Found: C, 59.27; H, 5.68. The 1H and
13C NMR spectra of this compound showed complex
patterns due to keto–enol tautomerism and doubling of
signals associated with the NCbz functionality.
3,6-Dideoxy-3,6-(N-benzylamino)-5,7-di-O-benzyl-1,2-
O-isopropylidene-a-D-glycero-d-glucohepto-1,4-
furanose (10): yield: 68%; white solid; mp 96–97 °C; Rf
0.70 (n-hexane–EtOAc, 19:1); [a]D +48.57 (c = 0.7, CHCl3).
IR (KBr): 1452, 1369, 1124, 1074, 698 cm–1. 1H NMR (300
MHz, CDCl3): d = 1.23 (s, 3 H), 1.45 (s, 3 H), 3.21 (ddd, app
q, J = 5.7, 6.3, 6.6 Hz, 1 H), 3.39 (d, J = 5.4 Hz, 1 H), 3.55
(dd, J = 6.3, 9.3 Hz, 1 H), 3.80 (dd, J = 5.7, 9.3 Hz, 1 H), 3.83
(d, J = 14.0 Hz, 1 H), 3.93 (dd, J = 4.8, 6.6 Hz, 1 H), 4.00 (d,
J = 14.0 Hz, 1 H), 4.15 (d, J = 3.6 Hz, 1 H), 4.45 (AB q, J =
12.0 Hz, 2 H), 4.53 (d, J = 12.0 Hz, 1 H), 4.75 (d, J = 12.0
Hz, 1 H), 4.78 (dd, J = 4.8, 5.4 Hz, 1 H), 5.85 (d, J = 3.6 Hz,
1 H), 7.20–7.40 (m, 15 H). 13C NMR (75 MHz, CDCl3): d =
26.6, 27.5, 57.7, 65.0, 70.8, 71.3, 72.7, 73.2, 78.0, 82.3, 84.8,
107.2, 112.0, 127.0, 127.3, 127.5, 127.7, 128.1, 129.2,
137.7, 138.0, 138.3. Anal. Calcd for C31H35NO5 (501.61): C,
74.23; H, 7.03. Found: C, 74.22; H, 7.00.
2,5-Dideoxy-2,5-imino-1,3-di-O-benzyl-l-glycero-a-D-
galactoheptitol (11): yield: 81%; viscous liquid; Rf 0.40
(n-hexane–EtOAc, 9:1); [a]D +3.07 (c = 0.65, CHCl3). IR
(neat): 3100–3550, 1639, 1456, 1369 cm–1. 1H NMR (300
MHz, CDCl3 + D2O): d = 3.02–3.12 (m, 2 H, H-3), 3.16
(ddd, J = 2.1, 4.2, 8.1 Hz, 1 H), 3.36 (dd, J = 2.7, 9.3 Hz, 1
H), 3.58 (d, J = 13.5 Hz, 1 H), 3.66 (dd, J = 4.5, 11.4 Hz, 1
H), 3.77 (dd, J = 4.5, 11.4 Hz, 1 H), 3.96 (ddd, app q, J = 4.5,
4.8, 9.6 Hz, 1 H), 4.01 (d, J = 13.5 Hz, 1 H), 4.05 (dd, J =
4.8, 8.1 Hz, 1 H), 4.22 (dd, J = 4.8, 5.1 Hz, 1 H), 4.44 (AB
q, J = 12.0 Hz, 2 H), 4.45 (d, J = 11.7 Hz, 1 H), 4.68 (d, J =
11.7 Hz, 1 H), 7.20–7.40 (m, 15 H). 13C NMR (75 MHz,
CDCl3 + D2O): d = 60.3, 63.3, 64.8, 67.1, 68.4, 69.4, 69.9,
71.9, 73.5, 77.7, 127.2, 127.5, 127.6, 127.7, 128.3, 129.7,
137.0, 137.7, 138.5. Anal. Calcd for C28H33NO5 (463.57): C,
72.55; H, 7.18. Found: C, 72.49; H, 7.15.
(24) All new compounds have been characterized by 1H NMR,
13C NMR, IR, and elemental analysis. Ethyl-3,6-dideoxy-3-
benzyloxycarbonylamino-1,2-O-isopropylidene-a-D-
xylohept-5-ulofuranuronate (7): viscous liquid; Rf 0.65
(n-hexane–EtOAc, 5:1); [a]D +3.33 (c = 0.60, CHCl3). IR
(neat): 3150–3400(br), 1730, 1650 cm–1. 1H NMR (300
MHz, CDCl3): d = 1.26 (t, J = 7.4 Hz, 3 H), 1.30 (s, 3 H),
1.50 (s, 3 H), 3.40 (d, J = 16.0 Hz, 1 H), 3.75 (d, J = 16.0 Hz,
1 H), 4.18 (q, J = 7.4 Hz, 2 H), 4.50–4.62 (br m, 2 H), 4.89
(d, J = 3.3 Hz, 1 H), 5.08 (AB quartet, J = 12.0 Hz, 2 H), 5.86
(d, J = 3.6 Hz, 1 H), 5.89 (d, J = 3.3 Hz, 1 H), 7.20–7.40 (br
s, 5 H). 13C NMR (75 MHz, CDCl3): d = 14.0, 26.1, 26.7,
46.8, 58.0, 61.7, 66.9, 83.5, 84.3, 104.7, 112.5, 127.8, 127.9,
128.3, 128.4, 135.9, 155.5, 167.3, 199.4. The 1H and 13
NMR spectrum showed additional signals (<5%)
C
corresponding to the enol form of the b-ketoester. Anal.
Calcd for C20H25NO8 (407.41): C, 58.96; H, 6.18. Found: C,
58.82; H, 6.12.
Ethyl-3,6-dideoxy-6-diazo-3-benzyloxycarbonylamino-
1,2-O-isopropylidene-a-D-xylohept-5-ulofuranuronate
(8): yield: 87%; viscous liquid; Rf 0.60 (n-hexane–EtOAc,
5:1); [a]D +44.00 (c = 0.5, CHCl3). IR (neat): 3150–3330,
2146, 1716, 1658 cm–1. 1H NMR (300 MHz, CDCl3): d =
1.38 (t, J = 6.9 Hz, 3 H), 1.35 (s, 3 H), 1.59 (s, 3 H), 4.32 (q,
J = 6.9 Hz, 2 H), 4.57 (d, J = 3.3 Hz, 1 H), 4.67 [(dd, J = 3.6,
8.7 Hz, 1 H); on D2O exchange became (d, J = 3.6 Hz)], 5.05
(s, 2 H), 5.22 (br d, J = 8.7 Hz, 1 H, exchanges with D2O),
5.69 (d, J = 3.6 Hz, 1 H), 5.97 (d, J = 3.3 Hz, 1 H), 7.20–7.40
(m, 5 H). 13C NMR (75 MHz, CDCl3): d = 14.6, 26.6, 27.1,
58.3, 62.4, 67.2, 80.0, 84.8, 104.6, 112.8, 128.1, 128.3,
128.7, 136.2, 155.6, 160.5, 186.1. In the 13C NMR the C5
carbon did not appear due to the presence of C=N2. This is
analogous to the earlier observation reported by Davis.2
Anal. Calcd for C20H23N3O8 (433.15): C, 55.42; H, 5.35.
Found: C, 55.32; H, 5.32.
Preparation of Ethyl-3,6-dideoxy-3,6-benzyloxy-
carbonylamino-1,2-O-isopropylidine-a-D-xylohept-5-
ulofuranuronate (9): To the solution of the diazo com-
pound 8 (1.00 g, 2.30 mmol) in anhyd benzene (5 mL) was
added Rh2(OAc)4 (0.03g, 0.04 mmol) under nitrogen
atmosphere and the solution was refluxed for 20 min. On
cooling, the reaction mixture was directly loaded on a silica
gel column and eluted (n-hexane–EtOAc, 7:3) to give 9 as a
viscous liquid (0.73 g, 78%); Rf 0.50 (n-hexane–EtOAc,
3:2); [a]D +10.00 (c = 0.8, CHCl3). IR (neat): 3150–3421
2,5-Dideoxy-2,5-imino-l-glycero-a-D-galactoheptitol
(12): yield: 85%; viscous liquid; Rf 0.10 (MeOH);
[a]D –86.66 (c = 0.6, H2O). IR (nujol): 3200–3600(br) cm–1.
1H NMR (300 MHz, D2O): d = 3.27 (dd, J = 5.7, 6.0 Hz,
1 H), 3.46 (ddd, app q, J = 5.8, 6.4, 6.6 Hz, 1 H), 3.63 (dd,
J = 6.6, 12.0 Hz, 1 H), 3.72–3.78 (m, 2 H, H-7b), 3.83 (dd,
J = 5.1, 11.4 Hz, 1 H), 3.97 (ddd, J = 3.3, 6.3, 9.9 Hz, 1 H),
4.29 (dd, J = 4.8, 5.7 Hz, 1 H), 4.35 (dd, J = 4.8, 6.6 Hz,
1 H). 13C NMR (75 MHz, D2O): d = 62.1, 62.3, 62.4, 65.8,
71.9, 73.7, 73.7. Anal. Calcd for C7H15NO5 (193.2): C,
43.52; H, 7.83. Found: C, 43.50; H, 7.81.
2,5-Dideoxy-2,5-imino-D-galactitol (14): yield: 83%;
viscous liquid; Rf 0.10 (MeOH). IR (nujol): 3200–3600(br)
cm–1. 1H NMR (300 MHz, D2O): d = 3.75–3.83 (m, 2 H, H-
2), 3.92 (dd, J = 8.4, 12.3 Hz, 2 H), 4.01 (dd, J = 5.1, 12.3
Hz, 2 H) 4.50 (dd, J = 1.5, 4.5 Hz, 2 H). 13C NMR (75 MHz,
D2O): d = 60.2, 63.8, 72.3. Anal. Calcd for C6H13NO4 (163):
C, 44.16; H, 8.03. Found: C, 44.17; H, 8.05.
2,5-Dideoxy-2,5-imino-D-galactitol Hydrochloride (15):
yield: 89%; semi solid. IR (nujol): 3200–3600(br) cm–1. 1H
NMR (300 MHz, D2O): d = 3.73–3.81 (m, 2 H), 3.90 (dd,
J = 8.1, 12.0 Hz, 2 H), 4.01 (dd, J = 4.8, 12.0 Hz, 2 H), 4.48
(d, J = 5.1 Hz, 2 H). 13C NMR (75 MHz, D2O): d = 57.8,
61.4, 70.0. Anal. Calcd for C6H14NO4Cl (199.5): C, 36.10;
H, 7.07. Found: C, 36.12; H, 7.07.
Synlett 2007, No. 4, 559–562 © Thieme Stuttgart · New York